Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic pertaining to the rifamycin class, specifically it is a pyrido-imidazo rifamycin which is described and claimed in the Italian Patent IT 1154655. European Patent EP 0161534 describes and claims a process for its production starting from rifamycin O (The Merck Index, XIII Ed., 8301).
Both of these patents describe the purification of rifaximin in a generic way stating that the crystallization can be carried out in suitable solvents or solvent systems and summarily showing in some examples that the product coming from the reaction can be crystallized from the 7:3 mixture of ethyl alcohol/water and can be dried both under atmospheric pressure and under vacuum. Neither of these patents disclose the experimental conditions of crystallization and drying, nor any distinctive crystallographic characteristic of the resulting product.
The presence of different polymorphs was previously unknown and therefore the experimental conditions described in both patents had been developed to produce a homogeneous product having a suitable purity from the chemical point of view, apart from the crystallographic aspects of the product itself.
It has now been found, unexpectedly, that some polymorphous forms exist whose formation, in addition to the solvent, depends on the conditions of time and temperature at which both the crystallization and the drying are carried out.
These orderly polymorphous forms are identified as rifaximin α (FIG. 1) and rifaximin β (FIG. 2) on the basis of their respective specific diffractograms, while the poorly crystalline form with a high content of amorphous component is be identified as rifaximin γ (FIG. 3) in the present application.
The polymorphous forms of rifaximin have been characterized using powder X-ray diffraction.
The identification and characterization of these polymorphous forms and, contemporarily, the definition of the experimental conditions for obtaining them is very important for a compound endowed with pharmacological activity which, like rifaximin, is marketed as a medicinal preparation both for human and veterinary use. It is known that the polymorphism of a compound that can be used as an active principle in a medicinal preparation can influence the pharmaco-toxicologic properties of the drug. Different polymorphous forms of an active principle can have different bioavailability, solubility, stability, colour, compressibility, flowability and workability with consequent modification of the profiles of toxicological safety, clinical effectiveness and productive efficiency.
The significance of different polymorphous forms is confirmed by the fact that the authorities which regulate the grant of authorization for the marketing of drugs require that the manufacturing methods of the active principles are standardized and controlled in such a way that they give homogeneous and sound results in terms of polymorphism of the production batches (CPMP/QWP/96, 2003—Note for Guidance on Chemistry of new Active Substance; CPMP/ICH/367/96—Note for guidance specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances; Date for coming into operation: May 2000).
The need for the above-mentioned standardization has been further strengthened, just in the field of rifamycin antibiotics, by Henwood S. Q., de Villiers M. M., Liebenberg W. and Lötter A. P., Drug Development and Industrial Pharmacy, 26 (4), 403–408, (2000), who have ascertained that different production batches of rifampicin (INN) made by different manufacturers show different polymorphous characteristics, and as a consequence they show different profiles of dissolution together with consequent alteration of the respective pharmacological properties.
By applying the processes of crystallization and drying generically disclosed in the previous patents IT 1154655 and EP 0161534 it has been found that under some experimental conditions the poorly crystalline form of rifaximin is obtained while under other experimental conditions the other crystalline polymorphous forms of rifaximin are obtained. Moreover it has been found that some parameters, which are not disclosed in the above-mentioned patents (e.g. the conditions of preservation and the relative humidity of the ambient) have a surprising effect on the form of the polymorph.
The polymorphous forms of rifaximin of the present patent application were not previously seen or hypothesized. The general thought at the time was that a sole homogeneous product would always be obtained regardless of which method was chosen within the range of the described conditions, irrespective of the conditions used for crystallizing, drying and preserving.
It has now been found that the formation of the α, β and γ forms depends on the presence of water within the crystallization solvent, on the temperature at which the product is crystallized and on the amount of water present into the product at the end of the drying phase.
The form α, the form β and the form γ of rifaximin have then been synthesised and they are the object of the present invention.
Moreover it has been found that the presence of water in rifaximin in the solid state is reversible, so that absorption and/or cession of water can take place under suitable ambient conditions. Consequently, rifaximin is susceptible to transition from one form to another, also remaining in the solid state, without the need to be dissolved and recrystallized. For example, the polymorph α, by adding water by hydration until a content higher than 4.5% is reached, turns into the polymorph β, which in its turn, loosing water by drying until a content lower than 4.5% is reached, turns into the polymorph α.
These results have a remarkable importance as they determine the conditions of industrial manufacturing of some steps which would previously not have been considered critical for the determination of the polymorphism of a product, like for instance the washing of a crystallized product, or the conditions of preservation of the end product, or the characteristics of the container in which the product is preserved.
The above-mentioned α, β and γ forms can be advantageously used as pure and homogeneous products in the manufacture of medicinal preparations containing rifaximin.
As previously indicated, the process for manufacturing rifaximin from rifamycin O disclosed and claimed in EP 0161534 is deficient from the point of view of the purification and identification of the product obtained. It shows some limits also from the synthetic point of view as regards, for instance, the very long reaction times, from 16 to 72 hours, which is unsuitable for industrial use and moreover because it does not provide for the in situ reduction of the oxidized rifaximin that may be formed within the reaction mixture.
Therefore, a further object of the present invention is an improved process for the industrial manufacturing of the α, β and γ forms of rifaximin, herein claimed as products and usable as defined and homogeneous active principles in the manufacture of the medicinal preparations containing such active principle.